As summarized in the Center Overview, schizophrenia appears to be associated with a reduction in the dopamine (DA) innervation of prefrontal cortex (PFC). However, the functional impact of such a deficit especially on other elements of PFC circuitry that are though to be dysfunctional schizophrenia, has not been well characterized. The proposed experiments will use a rat model and in vivo neurochemical methods to examine four questions relevant to this issue: (1) What is the impact of loss of DA axons in PFC on extracellular DA in this region? (2) What is the impact of this loss on the function of gamma-aminobutyric acid (GABA) interneurons in PFC? (3) Does loss of DA in PFC alter the ability of PFC to regulate the activity of one of its subcortical targets, the mesoaccumbens DA projection? (4) Does loss of DA axons in PFC sustained early in development produce changes in PFC function that are different from those seen in rats lesioned as adults? The neurochemical experiments described in the present project complement the studies of Projects Grace and Barrionuevo, which explore factors regulating the electrophysiological activity of PFC in rat and monkey. In addition, results of the proposed experiments will generate information about neurochemical interactions in the PFC of rat that will be used to guide the interpretation of data collected in behavioral and imaging studies in schizophrenic subjects (Projects-Cohen and Project-Sweeney), as well as to generate hypotheses regarding the neurochemical deficits of schizophrenia that may then be tested in functional imaging studies (Projects-Cohen and Sweeney) or be analysis of postmortem tissue (Project-Lewis).